Recent studies have shown that striatal nitric oxide (NO)-producing interneurons play an important role in modulating striatal neural activity and motor behavior. NO is a gaseous neurotransmitter produced by NO synthase (NOS) following glutamate receptor activation. NO diffuses freely through biological membranes and stimulates guanylyl cyclase (GC) and dopamine (DA) release processes critically involved in the generation of motor activity. Studies have shown that striatal NO interneurons receive inputs from the cortex and substantia nigra. However, the influence of these afferents on NOS activity remains to be determined. Additionally, the impact of NO-GC signaling pathways on the synaptic activity of medium spiny neurons (MSNs) is poorly understood. Therefore, the proposed studies plan to examine the afferent systems involved in activating striatal NOS and determine the impact of NO-GC signaling on MSN membrane activity using both in vivo and in vitro preparations. Aim 1 will utilize electrochemical microsensor measures of extracellular NO levels to determine the role of DA receptors in modulating the glutamatergic activation of striatal NOS. Aim 2 will use in vivo intracellular recording techniques in conjunction with microdialysis to determine the influence of NO signaling cascades on the bistable membrane activity of MSNs. Parallel studies will be performed in brain slice preparations to determine the role of GC signaling pathways in mediating the influence of NO on synaptic activity. We hypothesize that activation of corticostriatal afferents will augment striatal NO production in a manner that is differentially modulated by ongoing D1 and D2 DA receptor activation;moreover, activation of NO signaling will increase the excitability of MSNs via a GC-dependent mechanism, in a manner that is potentiated by D1 receptor activation. We believe that these studies will shed light on the mechanisms involved in the integration of dopaminergic and corticostriatal signaling by striatal neurons and suggest novel treatment strategies for Parkinson's disease.